Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

Abstract

Dysfunctional immune activity is a physiological component of both Alzheimer's disease (AD) and major depressive disorder (MDD). The extent to which altered immune activity influences the development of their respective cognitive symptoms and neuropathologies remains under investigation. It is evident, however, that immune activity affects neuronal function and circuit integrity. In both disorders, alterations are present in similar immune networks and neuroendocrine signalling pathways, immune responses persist in overlapping neuroanatomical locations, and morphological and structural irregularities are noted in similar domains. Epidemiological studies have also linked the two disorders, and their genetic and environmental risk factors intersect along immune‐activating pathways and can be synonymous with one another. While each of these disorders individually contains a large degree of heterogeneity, their shared immunological components may link distinct phenotypes within each disorder. This review will therefore highlight the shared immune pathways of AD and MDD, their overlapping neuroanatomical features, and previously applied, as well as novel, approaches to pharmacologically manipulate immune pathways, in each neurological condition. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

Creation of a gene expression portrait of depression and its application for identifying potential treatments

“…Among interesting GWAS genes is SPRY2, which is part of the MAP kinase pathway. Further, PSEN2 is noteworthy as it is linked to Alzheimer's disease and there is an emerging interest in intersections of depression and dementia 48 . In the depression portrait, PSEN2 is downregulate while PSEN1 is upregulated.…”

Incidence and Risk Factors for Dementia in Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Korea

“…In several longitudinal studies, depression was a major risk factor for incidence of dementia [34]. Depression was shown to injure neurons by several different mechanisms such as inflammation [35], elevated glucocorticoid production [36], amyloid deposition [37], or dysfunctional immune activity [38], which may lead to cognitive impairment. However, in a recent study, depression was a significant risk factor for YOD only if occuring within 10 years from YOD onset [32], indicating that depression might be a prodromal consequence of YOD rather than an etiological risk factor.…”

Immune dysregulation in depression: Evidence from genome-wide association

“…By activating cytokines and glucocorticoid release, stress and inflammation shift the balance of tryptophan metabolism towards kynurenine, whose levels are elevated relative to serotonin in depressed patients compared to controls ( Agudelo et al., 2014 ; Dantzer et al., 2008 ; Herbert and Lucassen, 2016 ; Kelly et al., 2016 ; Slavich and Irwin, 2014 ). Through various other effects of the kynurenine pathway, inflammation may impact depression symptoms including cognitive deficits, low mood, and sleep disturbances by promoting degradation of monoamines and melatonin, hippocampal atrophy, and production of endogenous NMDA-receptor agonists or antagonists ( Caumo et al., 2019 ; Herman et al., 2019 ; Jeon and Kim, 2017 ; Miller and Raison, 2016 ; Schlittler et al., 2016 ). The gut microbiome likely affects kynurenine metabolism and depression, as evidenced by the observation that fecal transplants from depressed people to rats raise their ratio of kynurenine to tryptophan and cause them to exhibit depressive behaviors ( Kelly et al., 2016 ), whereas probiotic treatment reduces expression of a kynurenine-synthesizing enzyme and depressive behavior ( Marin et al., 2017 ).…”